This study was designed to evaluate the effect of ligation of the carotid artery and/or jugular vein, after exposure to prolonged (4 hours) hypoxia, and the effect of acute normalization of Pao 2 after prolonged hypoxia with vessel ligation, on the cerebral circulation. Twelve 1- to 7-day-old lambs were anesthetized with pentobarbital. Catheters were placed in the femoral artery and vein, left ventricle, lingual artery, and sagittal sinus. Cerebral blood flow (CBF) was determined using the radiolabeled microsphere technique. After baseline studies, the animals were made hypoxic with a nitrogen/air mixture, to lower Pao 2 to 36 ± 5 mm Hg for 4 hours, followed by 1 hour of normoxia. After four hours of hypoxia, studies were performed. The animals were divided into two groups to evaluate carotid artery and jugular vein ligation separately. In group I, the carotid artery was ligated first, with studies performed after 5 minutes; this was followed by ligation of the jugular vein, with studies after 5 minutes. In group II, the jugular vein was ligated first, with studies after 5 minutes; this was followed by ligation of the carotid artery, with studies after 5 minutes. With regard to physiological variables, there were no differences between the groups. CBF increased 106% ( P < .001 compared with the baseline value) after 4 hours of hypoxia, maintaining cerebral oxygen consumption (CMRO 2) and oxygen transport (OT) constant in both groups. Ligation of either the carotid artery or jugular vein after 4 hours of hypoxia, did not alter CBF responses to hypoxia. There were no differences between right and left CBF after ligation with hypoxia. Cerebrovascular responses after the 1-hour recovery from hypoxia with vessel ligation were significant only in the cerebellar region, where CBF (mL/100 g/min) was significantly higher than the baseline value (baseline, 80 ± 21; normoxia, 115 ± 33; P < .003). These findings indicate that vessel ligation alone, after prolonged hypoxia, does not alter cerebrovascular responses in the newborn lamb, nor does it result in differences between right and left CBF. The cerebellar hyperemia during recovery from prolonged hypoxia, seen in this study, may indicate a risk for a reperfusion injury in this area of the brain.